Immunomodulatory derivatives (IMiDs), such as thalidomide, lenalidomide and pomalidomide have become an integral part of multiple myeloma (MM) treatment. Initially approved for relapsed/refractory setting, and later introduced into the upfront setting with and without transplant, IMiD based treatment combinations have produced unprecedented rates of disease response and progression free survival (PFS) benefit. Despite these therapeutic advances, the success of long-term treatment with IMiDs is limited by disease relapse and progression that occur almost universally at least due to innate or acquired drug resistance.
The precise mechanisms of IMiDs resistance are not entirely clear. Recently, it was shown that lenalidomide (Len) and other agents in the class of IMiDs mediate anti-myeloma effects through E3 ubiquitin ligase-cereblon to increase degradation of transcription factors Ikaros and Aiolos. However, attempts to accurately predict resistance based on expression level of individual predictive markers such as cereblon over-expression or deregulation of its downstream target IRF4 show contradictory results in different studies.
Several gene-expression profiling (GEP) signatures have been developed to stratify MM patients into different risk groups based on GEP samples from different clinical trials. These prognostic signatures are either focused on bortezomib (Bor) response genes or are more general to multiple agent chemotherapies used in the corresponding trials, but none of them are IMiDs specific. Recent studies on large-scale analysis of gene expression in MM have underscored the considerable potential of this strategy to elucidate resistance/response signature associated with IMiDs.
While the discovery of cereblon as a target of IMiDs has led to a better understanding of the molecular mechanism of action by these agents, the prognostic value of cereblon, Ikaros, or Aiolos is controversial. It has been previously shown that lenalidomide, and other agents in this class of IMiDs act through cereblon to increase the degradation of Ikaros and Aiolos transcription factors. However, low expression of cereblon, Ikaros and Aiolos in TT2 (thalidomide arm) and TT3a patients does not predict shorter PFS or overall survival (OS). Thus, there remains a need for improved methods for predicting resistance and/or response of MM to IMiDs treatment.
The present invention overcomes previous shortcomings in the art by providing methods for identifying IMiDs resistance in a subject.